Spill resistant formulations containing clays

ABSTRACT

The invention relates to novel spill resistant formulations comprising either a weak base or a weak acid as the pharmaceutical ingredient, a liquid base, a clay and a water soluble cellulose ether. The clay and cellulose ether allow for a broader pH range into which the pharmaceutically active agent may be dispersed or dissolved, and therefore allows for easier preparation and formulation of the pharmaceutical composition.

CROSS-REFERENCE TO RELATED APPLICATION

This claims the benefit of U.S. Provisional Application 60/514,999 filedOct. 28, 2003.

BACKGROUND OF THE INVENTION

Syrups, elixirs, solutions, and suspensions are traditional dosage formsfor oral medication. These liquid formulations are typically measured bypouring into a spoon, but this approach has the great drawback ofspillage. The risk of spillage can cause people to underfill or spillfrom the spoon, leading to inaccurate dosage. With elderly people,children, and the infirm, lack of motor skills or poor attention cancause difficulty in filling a spoon with a liquid and bringing it to themouth. This can result in a serious impediment to administering themedicine. Solid formulations such as pills, tablets, and capsules arealso difficult for children and for elderly, infirm people to swallow.

Recently, pharmaceutical preparations that are resistant to spilling forthe oral delivery of pharmaceutically active agents have been describedin the commonly owned U.S. Pat. Nos. 5,881,926, 6,071,523, 6,102,254,6,355,258, 6,399,079, and 6,656,482 incorporated herein in theirentirety by reference. U.S. Pat. Nos. 5,881,926 and 6,102,254 describe apharmaceutical delivery system for spill resistant formulations. U.S.Pat. Nos. 6,071,523, 6,355,258, 6,399,079 and 6,656,482 describe thespill resistant pharmaceutical compositions in terms of theirphysico-chemical properties and methods of preparing and using thoseformulations. These patents describe oral dosage forms for the deliveryof active agents that do not spill easily, are organoleptically pleasingand are storage stable.

The previously described spill-resistant pharmaceutical formulation fororal administration are from a squeezable container comprising aper-unit dose effective amount of a pharmaceutical agent in a suitablevehicle comprising a liquid base and a thickening or viscosity agent. Inthe previously described spill resistant formulations, the thickening orviscosity agent utilized most frequently was carbomer, a synthetic, highmolecular weight, polymer of acrylic acid cross-linked withallylsucrose. The viscosity of the carbomer gels are known to be pHdependent. Carbomer gels exhibit maximum viscosity at about neutral pH,where the viscosity plateaus between pH values of 6.3 to 7.0. ThispH-viscosity interaction of the carbomer polymer has restricted the useof weak acids and weak bases in spill resistant pharmaceuticalformulations. At higher or lower pH ranges, the ranges where the weakacids and bases are most soluble, the formulations lose their spillresistant properties. Now, using clays, we have expanded the pH rangeavailable for spill resistant formulations. This enables the developmentof spill resistant formulations where the pharmaceutical active agentshave either acidic or basic pKa's.

SUMMARY OF THE INVENTION

The invention provides for a pharmaceutical formulation, comprising aweakly basic pharmaceutically active ingredient, a liquid base, clay andat least one water soluble cellulose ether, wherein the pharmaceuticalformulation exhibits spill resistant characteristics.

The pharmaceutical formulation of the invention which comprises a weaklybasic pharmaceutically active ingredient, a liquid base, clay and atleast one water soluble cellulose ether, wherein the pharmaceuticalformulation exhibits spill resistant characteristics, and the pH of thepharmaceutical formulation is between about 3.0 to about 6.5.

An embodiment of the inventive pharmaceutical formulation is that thecomposition comprising a weakly basic active ingredient, a liquid base,a clay and at least one water soluble cellulose ether has a viscosity inthe range of from about 5,000 cps to about 25,000 cps. A furtherembodiment of the inventive pharmaceutical formulation is that thecomposition comprising a weakly basic active ingredient, a liquid base,a clay and one water soluble cellulose ether has a viscosity in therange of from about 5,000 cps to about 12,000 cps.

A further embodiment of the inventive formulation is that the weaklybasic pharmaceutically active ingredient, the liquid base, a clay andthe water soluble cellulose ether do not separate into separatecomponents after storage at room temperature for at least 24 month. In afurther embodiment of the inventive formulation, the weakly basicpharmaceutically active ingredient, the liquid base, the clay and thewater soluble cellulose ether do not separate under acceleratedstability conditions for at least 6 months.

In a specific embodiment of the invention, the pharmaceuticalformulation has a liquid base which is selected from a group consistingof glycerin, propylene glycol or sorbitol or mixtures thereof.

The invention provides for a pharmaceutical formulation comprising aweakly basic pharmaceutically active ingredient, a liquid base, a clayand a water soluble cellulose ether wherein the clay is selected fromthe group consisting of laponite, bentonite, montmorillonite, beidelite,hectorite, saponite and stevensite, and mixtures thereof.

Further, the inventive formulation comprises a weakly basicpharmaceutically active ingredient, a liquid base, a clay and a watersoluble cellulose ether, wherein the clay is laponite.

The pharmaceutical formulation of the invention which comprises a weaklybasic pharmaceutically active ingredient, a liquid base, a clay and atleast one water soluble cellulose ether, wherein the pharmaceuticalformulation exhibits spill resistant characteristics, and the pH of thepharmaceutical formulation is between about 3.0 to about 5.0.

The invention as described includes a weakly basic pharmaceuticallyactive ingredient selected from the group consisting of acyclovir,atenolol, atropine, ciprofloxacin, dilitiazem, diphenhydramine,diphenhydramine HCl, epinephrine, ephedrine, glucosamine, glucosaminesulfate, hydrochlorothiazide, metoprolol, nortriptyline, phenytoin,prednisone, propoxyphene, propranolol, terfenadine, tetracycline,pseudoephedrine and mixtures thereof.

More specifically, the inventive pharmaceutical formulation comprises:

-   -   (a) water in amounts from about 20% (w/w) to about 98% (w/w);    -   (b) glycerin in amounts from about 20% (w/w) to about 60% (w/w);    -   (c) clay in amounts from about 0.25% (w/w) to about 0.5% (w/w);    -   (d) water soluble cellulose ethers in amounts from about 0.8%        (w/w) to about 2.0% (w/w);    -   (e) an effective amount of a pharmaceutically active ingredient.

In another embodiment of the invention, the pharmaceutical formulationincludes the water soluble cellulose ether, carboxymethyl cellulose.

In another embodiment of the pharmaceutical formulation of the Inventionpropylene glycol may be used in the composition. Additionally, thepropylene glycol may be used in amounts of about 5% (w/w).Alternatively, sorbitol may be used in the pharmaceutical composition ofthe invention in amounts of about 5% (w/w).

The invention also provides for a pharmaceutical formulation, comprisinga weakly acidic pharmaceutically active ingredient, a liquid base, clayand at least one water soluble cellulose ether, wherein thepharmaceutical formulation exhibits spill resistant characteristics.

Furthermore, the pharmaceutical formulation comprising a weakly acidicpharmaceutically active ingredient, a liquid base, a clay and at leastone water soluble cellulose ethers, wherein the formulation may have apH of between about 7.5 to about 10.

The invention provides for a pharmaceutical formulation comprising aweakly acidic pharmaceutically active ingredient, a liquid base, a clayand at least one water soluble cellulose ether, wherein the viscosityranges from about 5,000 cps to about 25,000 cps. In a furtherembodiment, the viscosity ranges from about 5,000 to 12,000 cps.

In a further embodiment, the weakly acidic pharmaceutically activeingredient, the liquid base, the clay and the water soluble celluloseether pharmaceutical formulation will not separate into separatecomponents after storage at room temperature for at least 24 months.Additionally, the pharmaceutical formulation will not separate underaccelerated stability conditions for at least 6 months.

The pharmaceutical formulation of comprising a weakly acidicpharmaceutically active ingredient, a liquid base, clay and a watersoluble cellulose ethers wherein the liquid base is selected from agroup consisting of glycerin, propylene glycol or sorbitol.

Additionally, the pharmaceutical formulation comprising a weakly acidicpharmaceutically active ingredient, a liquid base, a clay and a watersoluble cellulose ethers, wherein the clay is selected from the groupconsisting of laponite, bentonite, montmorillonite, beidelite,hectorite, saponite and stevensite. More particularly, the clay may belaponite.

The weakly acidic pharmaceutically active ingredient of the inventiveformulation may be selected from the group consisting of captopril,diclofenac, enalapril, furosemide, ketoprofen, phenobarbital, naproxen,ibuprofen, lovstatin, penicillin G, piroxicam and ranitidine.

More particularly, the pharmaceutical formulation of the invention maycomprise:

-   -   (a) in amounts from about 40% (w/w) to about 98% (w/w);    -   (b) glycerin in amounts from about 20% (w/w) to about 60% (w/w);    -   (c) clay in amounts from about 0.25% (w/w) to about 0.5% (w/w);    -   (d) water soluble cellulose ethers in amounts from about 0.8%        (w/w) to about 2.0% (w/w);    -   (e) an effective amount of a pharmaceutically active ingredient.

In a further embodiment, the pharmaceutical formulation of the inventionhas carboxymethyl cellulose as the water soluble cellulose ether.

The pharmaceutical formulation of the present invention, comprising aweakly acidic a pharmaceutically active ingredient, a liquid base, aclay and a water soluble cellulose ether may further comprise propyleneglycol. The pharmaceutical formulation may have propylene glycol inamounts of about 5% (w/w).

Additionally, the pharmaceutical formulation comprising a weakly acidica pharmaceutically active ingredient, a liquid base, a clay and a watersoluble cellulose ethers may further comprise sorbitol in amounts ofabout 5% (w/w).

DETAILED DESCRIPTION

The pharmaceutical formulations of the present invention exhibit spillresistant characteristics. A spill-resistant pharmaceutical formulationaccording to the invention begins to spill from a spoon bowl during testperiods of vibrations, inversion, and tilting, but slowly enough toconform with practical time limits between dispensing and ingesting, andquickly enough to enable the product to be readily consumed from a spoonbowl.

Only certain pharmaceutical formulations can be prepared that have thephysico-chemical and rheological characteristics of a spill resistantpharmaceutical formulation. The physio-chemical and rheologicalcharacteristics of spill-resistant formulations are described in U.S.Pat. Nos. 6,071,523, 6,355,258, 6,399,079 and 6,656,482.

The physico-chemical and rheological characteristics which impart thespill resistant consistency of the formulation, permit the compositionto be squeezed into a spoon from a container with light manual pressure,to spread and level in a spoon bowl quickly enough for accuratemeasurement (typically in about 1-5 seconds at room temperature), and toremain in the spoon bowl long enough to permit administration withoutspilling particularly under difficult circumstances such as encounteredwith dispensing to children, or by the elderly. The elderly typicallyexhibit impaired movement either due to arthritis or tremors e.g.,essential tremor. The spill-resistant pharmaceutical formulation fororal administration from a squeezable container comprises a per-unitdose effective amount of a pharmaceutical agent in a suitable vehiclecomprising a liquid base and thickening or viscosity agents.

The formulation consists of mutually compatible components as describedbelow. The formulation has the following properties:

-   -   a) a viscosity within the range of about 5000 to about 25,000        cps using a Brookfield Viscometer with a ‘C’ spindle with        Helipath movement at a spindle speed of 20 rpm and 20-25 degree        centigrade;    -   b) a viscometric yield value of a semi-solid; a spill-resistant        consistency permitting the composition to be squeezed by light        manual pressure through a channel of about 1-5 mm;    -   c) the yield value allows the formulation to spread in a spoon        bowl sufficiently quickly for accurate measurement (1-5        seconds), and to remain in the spoon bowl without spilling for        several seconds (15-60) on spoon inversion (180 degrees) and        tilting at up to 90 degrees, preferably up to 30 seconds at 30        degrees, and for at least 50 seconds upon spoon vibration. The        shaking, tilting and inversion tests are performed on an        experimental platform as described in detail in U.S. Pat. No.        6,071,523;    -   d) homogeneity such that the components do not separate under        conditions of use;    -   e) and a storage stability such that the foregoing properties        are retained for at least two months of storage at accelerated        stability conditions of elevated temperature and humidity;

A spill-resistant formulation according to the invention begins to spillfrom a spoon bowl during test periods of vibrations, inversion, andtilting, but slowly enough to conform with practical time limits betweendispensing and ingesting, and quickly enough to enable the product to bereadily consumed from a spoon bowl by a patient. The spill resistantformulation is easy and accurate while dispensing and dosing to a 5.0 mLteaspoon.

The Brookfield viscosity of the pharmaceutical formulation falls withinthe range of about 5,000 centipoises (cps) to about 25,000 centipoises(cps) at room temperature. Viscosity is measured using a BrookfieldViscometer with a ‘C’ spindle with Helipath movement at 20 RPM and 20-25degree centigrade, or equivalent. Viscosity decreases slightly withincreasing temperature. Although spill resistant properties correlatewith viscosity, they are not necessarily directly linked to viscosity,so that compositions that fall within the target viscosity range maynevertheless lack spill resistance.

The flow quality of the formulation is a non-Newtonian, pseudoplasticand time independent fluidity wherein the viscosity of the non-solid geldecreases with increasing shear rate. The flow quality behavior is fullyreversible, and is indicative of Bingham behavior. Spill resistantpharmaceutical formulations are non-Newtonian and time independentfluids. Non-Newtonian refers to a fluid whose behavior departs from thatof an ideal Newtonian fluid. These fluids have different viscosities atdifferent shear rates and fall under two groups: time independent andtime dependent. Time independent fluids are those for which the rate ofshear at any point in the fluid is some function of the shear stress atthat point and depends on nothing else. These fluids have a constantviscosity value at a given shear rate. The viscosities do not changewith time. (McGraw-Hill Encyclopedia of Science & Technology, 6^(th)edition, 1987, Volume 12, pages 57-60).

Viscometric yield value means the ease of administration comprising (a)extrudability under light manual pressure from a squeezable container ora proxy (e.g. a syringe with a 5 mm orifice), and (b) spreadability in aspoon bowl measured by extruding the formulation into a spoon bowl anddetermining whether the material spreads to the edges of the spoon bowl.Yield value is the initial resistance to flow under stress. Yield valueis a measurable quantity similar to, but not dependent on, viscosity.The yield value of the spill resistant pharmaceutical formulations arefrom about 5 to about 200 D/cm² exhibits and exhibit Bingham behavior.Bingham plastics exhibit a yield stress, which is the stress that mustbe exceeded before flow starts, thereafter the rate-of-shear curve islinear. There are other materials that also exhibit a yield stress, butthe flow curve is thereafter not linear. These are usually calledgeneralized Bingham plastics. A Bingham flow requires an initial stress,the yield value, before it starts to flow. Once the yield value isexceeded and flow begins a Bingham fluid may display Newtonian,pseudoplastic or dilatant flow characteristics.

The spill resistant pharmaceutical formulations of the presentapplication have a pseudoplastic fluid's ratio of shear stress to therate of shear, which may be termed the apparent viscosity, fallsprogressively with shear rate. The decrease in viscosity with anincrease in shear rate is also known as shear thinning. This phenomenonof shear thinning is characteristic of formulations of asymmetricparticles or solution of polymers such as cellulose derivatives. Theviscosity of the spill resistant pharmaceutical formulation decreaseswith increasing shear rate, e.g., increasing the spindle speed. Thedesirable spill resistant properties occur at a viscosity greater thanabout 5,000 cps. The product spreads quickly at viscosity less thanabout 25,000 cps. Thus, spill resistance and spreading characteristicsare desirable in this viscosity range. The viscosity of the formulationincreases with decrease in temperature and decreases with increase intemperatures. However, these changes in the viscosity and correlatedspill resistant characteristics are reversible, so that the originalformula viscosity is obtained when temperature returns to roomtemperature (˜23° C.; broadly 19° C. to about 29° C.).

The composition has some or all of the following qualities. First, ifthe formulation is a suspension, the active ingredient is uniformlydispersed in the vehicle. The crystalline stability of the formulationis such that the active ingredient does not exhibit excessivecrystalline growth or dissolution so that the particles stay within atarget particle size range. The pharmaceutically active ingredientremains suspended indefinitely without agitation, that is withoutstirring or shaking. The uniformity of the formulation provides forconsistent dosing and increased shelf life of the product, as the activeingredient remains uniform per dose administered, and does not fall outof solution or separate from the suspension.

The antimicrobial activity of the spill resistant pharmaceuticalformulations meet standard microbial challenge requirements, such asthose described by the USP. The microbial challenge requirements may beeither due to preservatives or to a low water activity (about 0.60 toabout 0.84). Some preferred preservatives may be benzoic acid, sodiumbenzoate, sorbic acid, potassium sorbate, propionic acid, sodiumpropionate, ethyl alcohol, methylparaben, ethylparaben, propylparaben,and butylparaben. Other preservatives known in the art, may be used.These formulations may be alcohol-free to avoid complications from usingalcohol. The spill resistant formulations are palatable and have anacceptable taste and good mouthfeel.

Mutual compatibility of the components means that they do not separatein preparation and storage of the formulation for the equivalent of twoyears at room temperature (as indicated by six-months acceleratedstability testing at 40° C. and 75% relative humidity). Storagestability means that the materials do not lose their desirableproperties during storage for the same period. Preferred compositions donot exhibit a drop in viscosity of more than 50% or an increase inviscosity of more than 100% during that period. Additionally, thecomponents are mutually compatible in that they do not interfere withthe bioactivity of the pharmaceutical agent or physical properties ofthe vehicle. The components do not separate and retain the desiredphysico-chemical properties.

The pharmaceutically active ingredient of the spill-resistantpharmaceutical formulation of the present application will have a pKathat will not easily dissolve or disperse in a neutral pH. The solutionor suspension will be titrated to a pH of between 3.0 to 6.0 or,alternatively, from 7.5 to 10.0. The inventive formulation may include abuffer that will resist change of the pH on adding acid or alkali, or ondilution with a solvent. Examples of some commonly used pharmaceuticalbuffer systems are NH₄Cl, diethanolamine, triethanolamine, borate,carbonate, phosphorate, glutamate, succinate, malate, tartarate,glutarate, citrate, acetic acid, benzoate, lactate, glycerate, andgluconate. The pharmaceutical formulation thus formed will have enhancedstability because the pH is controlled in a narrow range.

Many drugs are weak acids or bases (Goodman & Gilman's, ThePharmacological Basis of Therapeutics, 10^(th) Edition, 2001). Acids aresubstances that are capable of donating protons and bases are substancesthat are capable of accepting protons. The strength of an acid or basevaries with the solvent. The strength of an acid depends not only on itsability to give up a proton, but also on the ability of the solvent toaccept the proton. The pH of the drug in aqueous solution will dependupon the disassociation constant of the drug in the solution. Weak acidsare soluble in basic aqueous solutions, whereas weak bases are moresoluble in acidic aqueous solution. Weak acids and weak bases arediscussed in detail in Physical Pharmacy. 4^(th) Edition, ed. AlfredMartin, Lippincott Williams & Wilkins, 1993, Chapter 7.

Examples of pharmaceutically active ingredients which may be suitablefor use in the present dosage forms includes, without limitation,analgesics, anti-inflammatories, antipyretics, antibiotics,antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics,antidiuretics, antiflatuents, antimigraine agents, antispasmodics,sedatives, antihyperactives, antihypertensives, tranquilizers,decongestants, beta blockers; peptides, proteins, oligonucleotides andother substances of biological origin, and combinations thereof.

Examples of pharmaceutically active ingredients that are weak basesinclude, acyclovir, atenolol, atropine, ciprofloxacin, dilitiazem,diphenhydramine, diphenhydramine HCl, epinephrine, ephedrine,glucosamine, glucosamine sulfate, hydrochlorothiazide, loratadine,metoprolol, nortriptyline, phenytoin, propoxyphene, propranolol,prednisolone, terfenadine, tetracycline, pseudoephedrine and mixturesthereof.

Examples of pharmaceutically active ingredients that are weak acidsinclude, captopril, diclofenac, enalapril, furosemide, ketoprofen,phenobarbital, naproxen, ibuprofen, lovstatin, penicillin G, piroxicamand ranitidine.

The pharmaceutical formulation described herein has a therapeutically orpharmacologically effective amount of either a water-soluble or waterinsoluble pharmaceutically active ingredient. By therapeutically andpharmacologically effective, it is meant the active ingredient ispresent in enough quantity, or concentration, to cause a response in aphysiologic system. It would be clear to one skilled in the art todetermine the pharmaceutically effective amount using known drugtherapies, e.g. The Physicians Desk Reference 2004, Thomson Healthcare;58th Bk&Cr edition.

Additional components of the pharmaceutical formulation may include oneor more of the following: surface active agents; dispersing agents;inert diluents; granulating and disintegrating agents; binding agents;lubricating agents; sweetening agents; flavoring agents; coloringagents; preservatives; physiologically degradable compositions such asgelatin; aqueous vehicles and solvents; oily vehicles and solvents;suspending agents; dispersing or wetting agents; emulsifying agents,demulcents; buffers; salts; thickening agents; fillers; emulsifyingagents; antioxidants; antibiotics; antifungal agents; stabilizingagents; pharmaceutically acceptable polymeric or hydrophobic materialsas well as other components. Ethylenediaminetetraacetic acid (EDTA) maybe used as a chelating agent because it forms stable water-solublecomplexes with alkaline earth and heavy metal ions.

The spill resistant pharmaceutical formulation contain thickening, orviscosity, agents which maintain the yield value of the formulation.Surprisingly, inorganic clays provide a stable vehicle at both an acidicpH as well as basic pH for the spill resistant formulations. Theinorganic clay may be selected from the group consisting of bentonite,laponite, montmorillonite, beidelite, hectorite, saponite andstevensite, or mixtures thereof. Hectorites and bentonites, bothsynthetic and natural, may be used as thickening agents. Examples of athickening, or viscosity, agent used to increase the viscosity of theformulation is a synthetic hectorite clay that imparts high shearthinning and thixotropic rheology to water based systems, such aslaponite. Hectorites having extra-small platelet size of 25×1 nanometerallows the formation of clear gels rather than opaque gel. The additionof small quantities of electrolytes allows for the formulation ofthixotropic clear gels. Hectorite clays are magnesium silicates with alayered structure and are marketed as granular, free flowing whitepowders. When dispersed in water the hectorites form thixotropic gels,or, if the sol forming grades are used, clear stable sols. These solscan be changed into thixotropic gels if or when required. The gelsystems produced form dispersions of these products in Bingham fluids.

In order to create a spill resistant formulation, various cellulosederivatives were experimented with in combination with the inorganicclays to impart a yield value to the gel. Hydroxypropyl cellulose (HPC),Hydroxypropylmethyl cellulose (HPMC) and Microcrystalline cellulose(also known as sodium carboxymethylcellulose (CMC)) were tested. All ofthe cellulose/clay combinations possessed gel like properties in thetest formulations. However, the HPC/clay and HPMC/clay compositions hadsome undesirable physical properties, i.e. the gels were stringy and/ornot clear. Additionally, the gels did not perform well on the spillresistant tests. The compositions tended to spread too quickly, or tooslowly. These results are demonstrated by Sample B-P in Table 1 andTable 2, below.

In contrast, the CMC/clay combination produced a clear gel with spillresistant like properties. The CMC/laponite combination will produce agelling agent that facilitates the formulation of basic active agents toproduce spill resistant gels at lower pH (from about pH 3.5 to about pH5.5) and with acidic active agents at higher pH (from about pH 7 toabout pH 10).

The pharmaceutical formulation may also comprise a carrier for thepharmaceutically active ingredient and the variety of other excipients.For example, propylene glycol may be used in amounts up to fifty (50)percent (w/w). Other excipients that may be used include glycerin andsorbitol. Either glycerin or sorbitol may be used in amounts of up toabout fifty (50) percent (w/w). Purified water is also added to thepharmaceutical formulation.

The pharmaceutical formulation may also comprise organolepticcomponents, which impart desirable sensory characteristics includingtaste, color, and smell. The organoleptic component may comprise a highintensity sweetener that improves sensory appeal such as sucraloseliquid concentrate. These components may also include coloring agentsthat provide desired coloring to the formulation. Flavoring agents suchas cherry flavor or a concentration of berry flavor, and taste maskingagents may be included.

Any conventional technique may be used for the preparation ofpharmaceutical formulations according to the invention. In general,preparation includes bringing the active ingredient into associationwith a carrier or one or more other additional components, and then, ifnecessary or desirable, shaping or packaging the product into a desiredsingle- or multi-dose unit. The active ingredient may be contained in aformulation that provides quick release, sustained release or delayedrelease after administration to the patient.

The pharmaceutical compositions may be prepared, packaged, or sold informulations suitable for oral, parenteral and topical administration.Other contemplated formulations include nanoparticles, liposomalpreparations, resealed erythrocytes containing the active ingredient,and immunologically-based formulations. A pharmaceutical composition ofthe invention may be prepared, packaged, or sold in bulk, as a singleunit dose, or as a plurality of single unit doses. A unit dose is adiscrete amount of the pharmaceutical composition comprising apredetermined amount of the active ingredient. The amount of the activeingredient in each unit dose is equal to the total amount of the activeingredient which would be administered or a convenient fraction of atotal dosage amount such as, for example, one-half or one-third of sucha dosage.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan, based on this disclosure, that such compositions aregenerally suitable for administration to any mammal. Preparation ofcompositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and perform such modifications with routine experimentation basedon pharmaceutical compositions for administration to humans.

EXAMPLES Example 1

The spill resistant-like properties of the hectorite gel, laponite, wereinvestigated. Laponite gel samples were compounded either with carbomer,sodium carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) andhydroxypropyl methylcellulose (HPMC) as described below:

-   -   A. weigh and measure clay and water to a stainless steel vessel        and mix until a clear solution is formed. Crystalline sorbitol        is added after the clay dissolves, and the solution is mixed        until a clear solution is formed;    -   B. add sodium carboxymethylcellulose (CMC),        hydroxypropylcellulose (HPC), or hydroxypropyl methylcellulose        (HPMC) to solution A until a uniform dispersion forms;    -   C. add glycerin, propylene glycol and citric acid, to dispersion        B and mix until a uniform dispersion is achieved.

Examples of spill resistant formulations using a combination ofcellulose and laponite thickening agents, in varying quantities, aregiven in Table 1. The experimental laponite containing spill resistantformulations described in Table 1, containing either a) carbomer, b)sodium carboxymethylcellulose (CMC), c) hydroxypropylcellulose (HPC) ord) hydroxypropyl methylcellulose (HPMC) were compared against a controlspill resistant formulation containing the active ingredient,Pseudoephedrine, and the thickening agent, carbomer (as described inpublished U.S. Patent Publication No. US20030235618A1, herebyincorporated by reference).

As shown in Table 2 the control spill resistant preparation containingpseudoephedrine exhibited the following characteristics: (i) a viscosityof 11,350 cps; (ii) a spreading of 2 seconds; (iii) an inversion time ofgreater than 60 seconds; (iv) a tilting time of greater than 60 seconds;and (v) a shaking time of 60 seconds.

As observed, all of the experimental laponite pharmaceutical formulationsamples formed gels when mixed with water. However, the HPMC/laponitegels were translucent and did not meet the spill resistant criteria ofthe testing (see Tables 1 and 2—Samples B and C).

HPC/laponite formulations tended to be more filamentous than the gelsprovided by other cellulose ethers. However, it was observed that 2% HPC/0.5% laponite (Table 1 sample G) did provide for an acceptable spillresistant composition (Table 2, Sample G).

A synergistic rheology was perceived with the CMC/laponite gels (seeTables 1 and 2 samples M-T). Experimentally, increasing the amount ofthe CMC in the formulation appeared to have a detrimental effect on thespill resistant characteristics. Sample M containing 1.5% CMC/0.25%laponite and Sample N containing 2% CMC/0% laponite, both resulted insmooth clear gels that either did not spread in the spoon, or fell offthe spoon too quickly on inversion (see example M and N; Tables 1 and2).

Specifically, the spill resistant gels exhibited the followingcharacteristics: (i) a viscosity between 6,800 cps (sample G) and 15,240cps (sample T); (ii) a spreading in the spoon bowl of less than 4seconds; (iii) an inversion time of greater than 60 seconds; (iv) atilting time of greater than 60 second; and (v) a shaking time ofgreater than or equal to about 50 seconds.

Spill Resistant formulations existed at both basic pH (samples G and K),and acidic pH (samples L, O-T). The pH values of all the samples withoutthe addition of citric acid were in the ranges of 9.26 to 9.89. It ispossible to increase the pH to greater than 9.9 with the addition ofNaOH, or other suitable bases. Citric acid was added to the Samples J,L, O, P, Q, R, S, and T to reduce the pH to an acidic value. No adverseeffect was observed by the addition of the acid.

TABLE 1 Compositions containing carbomer, sodium carboxymethylcellulose(CMC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose(HPMC), respectively. Water Glycerin Sample (%) (%) Laponite (%) OtherIngredient (%) Observations Control 0.26% 33.38 50 0 0.33 (carbomer)Smooth clear gel Pseudoephedrine 0.27 (NaOH) 3.0 (sucralose) A 38.5 50.01.5 0.2 (carbomer) Smooth clear gel 0.1 (NaOH) 5.0 (propylene glycol) B57.0 40.0 1.5 1.5 (HPMC) Aerated translucent smooth gel C 98.0 0 0.5 1.5(HPMC) Translucent smooth gel D 58.5 40.0 0.5 1.0 (HPC) Translucent gelwith slimy filament texture E 58.0 40.0 0.5 1.5 (HPC) Translucent gelwith slimy filament texture F 58.0 40.0 0.5 1.5 (HPC) Translucent gelwith slimy filament texture 0.04 (Citric acid) G 97.5 0 0.5 2.0 (HPC)Aerated viscous translucent gel H 98.0 0 0 2.0 (HPC) Smooth soft cleargel I 98.0 0 0.5 1.5 (CMC) Rigid smooth clear gel, very thixotropic J98.0 0 0.5 1.5 (CMC) Rigid smooth clear gel, very thixotropic 0.04(Citric acid) K 98.5 0 0.5 1.0 (CMC) Rigid smooth clear gel, verythixotropic L 98.5 0 0.5 1.0 (CMC) Rigid smooth clear gel, verythixotropic 0.04 (Citric acid) M 98.3 0 0.25 1.5 (CMC) Smooth clear gelN 98.0 0 0 2.0 (CMC) Smooth soft clear gel O 78.5 20.0 0.5 1.0 (CMC)Smooth clear gel 0.04 (Citric acid) P 58.8 30 0.25 0.8 (CMC) Smoothclear gel 5.0 (Propylene glycol) 5.0 (Sorbitol) 0.2 (Citric acid) Q 58.540.0 0.5 1.0 (CMC) Smooth clear gel 0.04 (Citric acid) R 58.5 40.0 0.51.0 (CMC) Smooth clear gel, palatable taste, slightly 0.14 (Citric acid)starchy mouth-feel S 58.3 40 0.25 1.3 (CMC) Smooth clear gel 0.2 (Citricacid) T 58.5 30 0.25 1.1 (CMC) Smooth clear gel 5.0 (Propylene glycol)5.0 (Sorbitol) 0.2 (Citric acid)

TABLE 2 Spill Resistant Formulations Viscosity¹ Spreading InversionTilting Shaking Spill Resistant Sample pH (cps) (sec.) (sec.) (sec.)(sec.) Characteristics Control 0.26% 6.10 11350 2 >60 >60 >60 YesPseudoephedrine A 5.82 10540 1.5 >60 >60 51 Yes B 9.60 292504 >60 >60 >60 No C 9.89 8130 1.5 8 20 >60 No D 9.26 10590 1.5 5 11 6 NoE 9.31 27170 3 36 >60 >60 No F 3.49 22230 2 16 36 >60 No G 9.55 68002 >60 >60 >60 Yes H 6.09 8250 1.5 5 9 >60 No I 9.55 22540 >4 >60 >60 >60No J 5.61 21390 >4 >60 >60 >60 No K 9.57 12290 4 >60 >60 >60 Yes L 5.4311540 4 >60 >60 >60 Yes M 9.40 19920 >4 >60 >60 >60 No N 6.65 12320 1.519 29 >60 No O 6.32 14530 4 >60 >60 >60 Yes P 4.37 9550 1.5 >60 >60 51Yes Q 6.21 12680 2 >60 >60 >60 Yes R 4.78 11820 2 >60 >60 >60 Yes S 4.4016780 2.5 >60 >60 >60 Yes T 4.50 15240 2 >60 >60 >60 Yes ¹Brookfieldviscometer Vis02, Spindle C @ 20 rpm at RT.

Example 2

Acyclovir is an active agent that is a weak base, and is thus poorlysoluble at the optimal pH range for a carbomer based spill resistantformulation. A more acidic pH for the pharmaceutical formulation isdesired to achieve a stable, spill resistant acyclovir formulation withthe proper viscosity. We anticipate that a pH of 3.0 to 3.5 would bedesirable for formulation of the suspension. A suspension of 200 mg/mlof the antiviral agent acyclovir will be used in a spill resistantpharmaceutical formulation containing CMC/clay as the thickening agent.As a formulation, the following ingredients will be used to form a spillresistant 200 mg/5 ml acyclovir suspension.

TABLE 3 Proposed 200 mg/5 ml Acyclovir Spill Resistant FormulationSample A Ingredients % (w/w) Water 30.93 Glycerin 50.0 Polyethyleneglycol 1000 15.0 Laponite 0.25 Carboxymethylcellulose 1.1 Sucralose 0.5Citric Acid 0.4 Initial viscosity at 23° C., cps 11000

Stabilizers, anti-microbials, organoleptic and other excipients will beadded as needed. The formulation will have the spreading, tilting,shaking and consistency of a spill resistant formulation, as shown inTable 4.

TABLE 4 Spill Resistant Characteristics for an Acyclovir SuspensionViscosity¹ Spreading Inversion Tilting Shaking Lot # pH (cps) (sec.)(sec.) (sec.) (sec.) Acyclovir 3.25 11000 2 >60 >60 >60

Example 3 Stability Testing

Stability testing will done at 0 months, 6 months, 12 months and 18months post manufacturing of Exhibit Samples of an Acyclovir SuspensionFormulation. The following tests will be done:

-   -   A. Description of physical properties of product.    -   B. pH of the undiluted product will measured using pH-meter.    -   C. Viscosity will be measured using a Brookfield Viscometer with        a ‘T-C’ spindle 20 RPM at 20-25° C.    -   D. Impurities will be measured by reverse-phase HPLC, using a C        column with an organic mobile phase, eluting at appropriate        times for the column wash, with detection by UV absorption.        Samples will be prepared for analysis by dissolving of product        in the sample solvent and subsequent dilution in the sample        solvent to desirable concentration. Retention time of        preservatives, active agents and any identified impurities will        be calibrated.    -   E. Bottle uniformity is a measure of the any active agent at the        top, middle and bottom levels of the bottle. Amount of        pharmaceutically active ingredients will be measured by HPLC as        explained above (step D).    -   F. Dissolution—amount of dissolved active (% label claim) will        be adopted directly from the USP Dissolution procedure.        Dissolution testing will measure the amount of pharmaceutical        active ingredient dissolved in 60 minutes in a dissolution        apparatus using a spindle at 50 rpm (revolutions per minute) at        37° C. A dissolution apparatus (Distek Inc., North Brunswick,        N.J.), equipped with 6 to 8 vessels immersed in a water bath and        maintained at 37±0.5° C., and individual spindles for each        vessel will be employed for the testing. Samples will be taken        by syringe at regular intervals from each vessel and measured by        HPLC. An example of desired stability data is given in Table 5.

TABLE 5 Stability Data Parameter 0 Months 6 Months 12 Months 18 Months24 Month Description Orange, Orange, opaque, Orange, opaque, Orange,opaque, Orange, opaque, opaque, viscous, jellylike viscous, jellylikeviscous, jellylike viscous, jellylike viscous, material with materialwith material with material with jellylike characteristic characteristiccharacteristic characteristic material with berry odor berry odor berryodor berry odor characteristic berry odor pH 3.2 3.2 3.2 3.2 3.2Viscosity 11000 cps 11000 cps 11000 cps 11000 cps 11000 cps Acyclovir 99.1% 101.5% 101.9% 102.1% 102.1% (mean of Bottle Uniformity) BottleTop: 99.1% Top: 101.5% Top: 100.6% Top: 98.9% Top: 98.9% UniformityMiddle: Middle: 102.6% Middle: 101.8% Middle: 102.2% Middle: 102.2%(with 99.0% Bottom: 101.9% Bottom: 103.2% Bottom: 105.2% Bottom: 105.2%relative Bottom: 99.2% % RSD 1.3% % RSD 1.3% % RSD 3.1% % RSD 3.1%standard % RSD 0.1% deviation) Bottle Top: 99.1% Top: 101.5% Top: 100.6%Top: 98.9% Top: 98.9% Uniformity Middle: Middle: 102.6% Middle: 101.8%Middle: 102.2% Middle: 102.2% (with 99.0% Bottom: 101.9% Bottom: 103.2%Bottom: 105.2% Bottom: 105.2% relative Bottom: 99.2% % RSD 1.3% % RSD1.3% % RSD 3.1% % RSD 3.1% standard % RSD 0.1% deviation) Butylparaben103.1% 104.4% 104.6% 103.4% 103.4% Assay Dissolution V₁ = 96% V₁ = 102%V₁ = 102% V₁ = 102% V₁ = 102% (vessels V₂ = 96% V₂ = 102% V₂ = 102% V₂ =102% V₂ = 102% (V₁₋₆)) V₃ = 96% V₃ = 102% V₃ = 102% V₃ = 102% V₃ = 102%V₄ = 97% V₄ = 100% V₄ = 102% V₄ = 102% V₄ = 102% V₅ = 102% V₅ = 101% V₅= 102% V₅ = 102% V₅ = 102% V₆ = 99% V₆ = 101% V₆ = 102% V₆ = 102% V₆ =102% Microbiological Less than 10 Less than 10 Less than 10 Less than 10Less than 10 Examination microorganisms/g microorganisms/gmicroorganisms/g microorganisms/g microorganisms/g (no Salmonella (noSalmonella (no Salmonella (no Salmonella or (no Salmonella or E. Coli)or E. Coli) or E. Coli) E. Coli) or E. Coli) Impurity 1 Not detectedLess than Not detected Not detected Not detected 0.050% Impurity 2 Lessthan Less than Less than Not detected Not detected 0.050% 0.050% 0.050%Total Less than Less than Less than Not detected Not detected Impuities0.050% 0.050% 0.050%

In describing embodiments of the present invention, specific terminologyis employed for the sake of clarity. However, the invention is notintended to be limited to the specific terminology so selected. It is tobe understood that each specific element includes all technicalequivalents, which operate in a similar manner to accomplish a similarpurpose. The above-described embodiments of the invention may bemodified or varied, and elements added or omitted, without departingfrom the invention, as appreciated by those skilled in the art in lightof the above teachings. Each reference in its entirety, cited here isincorporated by reference as if each were individually incorporated byreference.

1-31. (canceled)
 32. A pharmaceutical formulation, comprising apharmaceutically active ingredient, clay and at least one water solublecellulose ether, wherein the viscosity of the pharmaceutical formulationranges from about 5,000 cps to about 25,000 cps.
 33. The pharmaceuticalformulation of claim 32, wherein the viscosity is measured using aBrookfield viscometer at a spindle speed of 20 rpm.
 34. Thepharmaceutical formulation of claim 32, wherein the pharmaceuticalformulation exhibits spill resistant characteristics.
 35. Thepharmaceutical formulation of claim 32, wherein the pharmaceuticallyactive ingredient is weakly basic.
 36. The pharmaceutical formulation ofclaim 35, wherein the weakly basic pharmaceutically active ingredient isselected from the group consisting of acyclovir, atenolol, atropine,ciprofloxacin, dilitiazem, diphenhydramine, diphenhydramine HCl,epinephrine, ephedrine, glucosamine, glucosamine sulfate,hydrochlorothiazide, metoprolol, nortriptyline, phenytoin, propoxyphene,propranolol, terfenadine, tetracycline, pseudoephedrine and mixturesthereof.
 37. The pharmaceutical formulation of claim 32, wherein thepharmaceutically active ingredient is weakly acidic.
 38. Thepharmaceutical formulation of claim 37, wherein the weakly acidicpharmaceutically active ingredient is selected from the group consistingof captopril, diclofenac, enalapril, furosemide, ketoprofen,phenobarbital, naproxen, ibuprofen, lovastatin, penicillin G, piroxicam,ranitidine and mixtures thereof.
 39. The pharmaceutical formulation ofclaim 32, wherein the viscosity of the pharmaceutical formulation rangesfrom about 5,000 cps to about 17,000 cps.
 40. The pharmaceuticalformulation of claim 32, wherein the pharmaceutically active ingredient,the clay and the water soluble cellulose ether do not separate afterstorage at room temperature for at least twenty-four months.
 41. Thepharmaceutical formulation of claim 32, wherein the pharmaceuticallyactive ingredient, the clay and the water soluble cellulose ether do notseparate under accelerated stability conditions for at least 6 months.42. The pharmaceutical formulation of claim 32, comprising a liquidbase.
 43. The pharmaceutical formulation of claim 42, wherein the liquidbase comprises one or more components selected from the group consistingof glycerin, propylene glycol, sorbitol and mixtures thereof.
 44. Thepharmaceutical formulation of claim 32, wherein the clay is selectedfrom the group consisting of laponite, bentonite, montmorillonite,beidelite, hectorite, saponite, stevensite and mixtures thereof.
 45. Thepharmaceutical formulation of claim 32, wherein the water solublecellulose ether is carboxymethyl cellulose.
 46. The pharmaceuticalformulation of claim 32, wherein the pH of the pharmaceuticalformulation is between about 3.0 and about 6.5.
 47. The pharmaceuticalformulation of claim 32, wherein the pH of the pharmaceuticalformulation is between about 7.5 and about
 10. 48. The pharmaceuticalformulation of claim 32, comprising: (a) from about 20% (w/w) to about98% (w/w) water; (b) from about 20% (w/w) to about 60% (w/w) glycerin;(c) from about 0.25% (w/w) to about 0.5% (w/w) clay; (d) from about 0.8%(w/w) to about 2.0% (w/w) of one or more water soluble cellulose ethers;and (e) an effective amount of at least one pharmaceutically activeingredient.